The present invention relates to stable salts of O-acetylsalicylic acid with basic amino acids, a process for their preparation, and their use as medicaments.
The analgesic action of O-acetylsalicylic acid (Aspirin(copyright)) has been utilized therapeutically for a long time. Thus O-acetylsalicylic acid is used as an analgesic, antipyretic, antirheumatic, and also as a non-steroidal anti-inflammatory agent, for example for the treatment of arthritis, neuralgia and myalgia.
However, O-acetylsalicylic acid is only soluble to a limited extent and thus is only suitable for oral administration. However, it has been disclosed (cf. JP-A-48056815) that salts of O-acetylsalicylic acid with basic amino acids are suitable for parenteral administration. As basic amino acids, in particular L-lysine, D,L-lysine and arginine are employed. A certain proportion of glycine can also be added.
Salts of O-acetylsalicylic acid with basic amino acids have been used for a long time in various indications, for instance in the abovementioned indications. The good solubility of these O-acetylsalicylates is an advantage here compared with O-acetylsalicylic acid, in particular in the case of parenteral administration. Moreover, in the case of relatively long oral administration good tolerability of the O-acetylsalicylates is to be emphasized.
A certain disadvantage of the O-acetylsalicylates until now was their inadequate stability. On the one hand, a restricted shelf life of the pharmaceutical preparations produced from these salts results from this. On the other hand, sterilization of the active compound, which may be necessary, cannot be carried out by means of heat sterilization because of the inadequate thermal stability of these salts, but must be carried out in other ways, for example by introduction of ethylene oxide gas.
The low stability of the O-acetylsalicylates is to be attributed to a back reaction of the product to O-acetylsalicylic acid and the corresponding amino acids known to the person skilled in the art. The amino acid then reacts with the O-acetylsalicylic acid with removal of the acetyl group (amidolysis) and release of salicylic acid. The presence of salicylic acid in pharmaceutical preparations, however, is undesirable and therefore to be restricted to a low, acceptable value. It is known that this degradation reaction is pH-dependent (F. Moll, Arch. Pharm. 318 (1985), 120-127). A lowering of the pH leads to an increased protonation of the amino acid released, so that this is not available or only available to a very restricted extent for the subsequent reaction with the O-acetylsalicylic acid. The amidolysis and thus the release of salicylic acid is thereby suppressed.
To increase the stability of pharmaceutical preparations which contain O-acetylsalicylates, the addition of xe2x80x9cacidicxe2x80x9d stabilizers such as calcium chloride has therefore been proposed in the past (cf. U.S. Pat. No. 4,265,888). The presence of Ca ions in the product, however, is not acceptable for the treatment of cardiovascular diseases.
It has likewise been postulated that the moisture content of the O-acetylsalicylate products has a considerable influence on their stability. Another way to increase the stability of the O-acetylsalicylates would therefore consist in the reduction of the residual moisture content by drying at a high temperature. Intensive drying at elevated temperature, however, because of the instability of the salts already mentioned above at the temperatures necessary therefor, leads to the desired goal only to a limited extent or not at all.
It was therefore the object of the present invention to make available compositions which comprise a salt of O-acetylsalicylic acid with a basic amino acid, and which have increased stability and therefore do not have the disadvantages of the O-acetylsalicylates known until now with respect to storage and/or sterilizability.
This object is achieved according to the present invention by a composition comprising a salt of O-acetylsalicylic acid with a basic amino acid, the salt having an average particle size above a particle size of 160 xcexcm and a proportion of more than 60% of the particles having a particle size in a range from 100 to 200 xcexcm in a particle size distribution measured using a Malvern 2600D apparatus under standard conditions.
According to the invention, compositions are preferred here in which the salt of O-acetylsalicylic acid with a basic amino acid contained therein has an average particle size above a particle size of 170 xcexcm and a proportion of more than 70% of the particles having a particle size in a range from 100 to 200 xcexcm in a particle size distribution measured using a Malvern 2600D apparatus under standard conditions.
The present invention is illustrated in greater detail by the accompanying figures, in which;
FIG. 1 shows a graphic representation of the particle size distribution of the O-acetylsalicylate prepared according to Ex. 1 in comparison with the particle size distribution of a commercially available O-acetylsalicylate (Aspisol(copyright))
FIG. 2 shows the integrals of the curves of the particle size distributions shown in FIG. 1 for Ex. 1 according to the invention and Aspisol(copyright)
FIGS. 3 and 4 show illustrations of crystals of an O-acetylsalicylate according to Ex. 1 of the present invention.
FIGS. 5 and 6 show illustrations of crystals of Aspisol(copyright) . The particle size analyses shown in FIGS. 1 and 2 were carried out using the same crystals.
FIG. 7 shows a graphic representation of the stability at various temperatures. The change in the content of free salicylic acid (in %) in an O-acetylsalicylate according to Ex. 3 of the present invention and in Aspisol(copyright) is indicated.